Project Summary Osteoporosis, a degenerative disease resulting from an imbalance of bone formation relative to bone resorption, will strike an estimated 50% of Americans over the age of 50. Although fractures call forth images from childhood of a limb in a cast, soliciting autographs and sympathy during a brief period of recovery, fragility fractures in the elderly are far more sinister. The one-year mortality rate for patients over the age of 50 with a hip fracture is an astounding 24%, and only one in three regain their pre-fracture ability to function independently. As lifespans lengthen and the population ages, the costs of osteoporotic fractures - already over $18 billion annually - will surely rise. Current therapies for osteoporosis are mostly anti-resorptive, and therefore not curative. With the recent approval of recombinant human parathyroid hormone (teriparatide, PTH[1-34]), an anabolic agent with potent stimulatory effects on bone formation is now available. However, limitations due to parenteral administration and a potential concern for osteogenic malignancies all point to an enduring need for additional therapies for osteoporosis. The canonical Wnt signaling pathway also has a critical role in bone formation, thus targeting the Wnt pathway is an attractive option for treating osteoporosis. Recent studies have highlighted an important role for sclerostin, an inhibitor of Wnt signaling, and evidence that PTH suppresses sclerostin expression suggests that meaningful cross-talk exists between these two pathways. The heterotrimeric G protein Gs1 is a major downstream mediator of PTH signaling via the PTH/PTH-related peptide receptor. I have found that ablation of Gs1 in the osteoblast lineage in mice (Gs1 KO mice) leads to profound osteoporosis;in these mice sclerostin expression is markedly increased, with a resultant decrease in canonical Wnt signaling. Since the PTH and Wnt pathways likely have both overlapping and distinct actions on bone formation, in this application I propose to determine how inhibition of Wnt signaling by sclerostin contributes to the dramatic reduction of bone mass in Gs1 KO mice. I propose to cross Gs1 KO mice with mice lacking sclerostin (SOST KO mice). In Aim 1 I will examine the role of sclerostin in embryonic skeletal development of Gs1 KO mice. In Aim 2 I will delay ablation of Gs1 in osteoprogenitors until birth, to specifically focus on the function of sclerostin in postnatal skeletal homeostasis. In Aim 3 I will harvest bone marrow stromal cells and calvarial osteoblasts from single and double KO mice to establish how PTH and Wnt signaling pathways interact to regulate mesenchymal lineage commitment and osteogenic differentiation. Understanding the molecular mechanisms underlying the anabolic effects of PTH and Wnt signaling may eventually provide additional targets for the treatment of osteoporosis. PUBLIC HEALTH RELEVANCE: Project Narrative Osteoporosis is a common degenerative disease of aging, and treatments available to cure this debilitating disease are lacking. Parathyroid hormone and the Wnt signaling pathway both act to control bone formation. This proposal seeks to understand how these two pathways interact at the molecular level, as greater insights into the processes by which bone mass is increased may ultimately result in novel therapies for osteoporosis.